Plasma cross-linked hydrophilic coating

ABSTRACT

A method for making a hydrophilic and lubricious coating, the coating so made and a medical device including such coating, wherein the coating includes a hydrophilic polymeric unit layer cross-linked with a plasma deposited double bond monomer. The hydrophilic polymeric unit can include ethylene oxide with one or more primary or secondary alcohol groups or glycosaminoglycans such as hyaluronic acid, and the double bond monomer includes monomers containing at least one double bond, preferably a C═C, C═N or C═O bond, including N-trimethylsilyl-allylamine, ethylene, propylene and allyl alcohol. The invention also provides products containing such coatings and their uses in medical, pharmaceutical and cosmetic applications.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication Serial No. 60/326,048, entitled “Plasma Cross-LinkedHydrophilic Coating”, filed on Sep. 28, 2001, and the specificationthereof is incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention (Technical Field)

The present invention relates to materials, methods and processes formaking a hydrophilic and lubricious coating, wherein a hydrophilicpolymeric unit is cross-linked by means of a plasma process with adouble bond monomer, wherein the coating optionally further includes abifunctional spacer to which the hydrophilic polymeric unit is bound.Also provided is the hydrophilic and lubricious coating and medicaldevices including the coating.

2. Background Art

Note that the following discussion refers to a number of publications byauthor(s) and year of publication, and that due to recent publicationdates certain publications are not to be considered as prior artvis-a-vis the present invention. Discussion of such publications hereinis given for more complete background and is not to be construed as anadmission that such publications are prior art for patentabilitydetermination purposes.

For many medical devices, it is preferable if a coating or othercontacting surface has several properties, including biocompatibilityand lubricity. Device surfaces and coatings that are water absorbent andlubricious may be effectively employed with, for example, stents,screws, tubing, catheters, wire guides, needles, sutures, and the like.Coatings that are hydrophilic and lubricious can be contacted withtissues with decreased trauma. For example, any medical device, such asa bandage, suture, tubing, catheter, guide wire and the like, may bemore conveniently removed with less trauma to associated tissue if thesurface is lubricious.

Similarly, it is a requirement for medical device surfaces that thesurface or other coating be biocompatible. Any implantable medicaldevice requires biocompatibility, in order to avoid adverse reactions.In normal application, such devices are expected to function in intimatecontact with living tissue and blood. This contact requires a delicatebalance between ensuring that the device can function in the complexextra- and intra-cellular environment and maintaining the living tissuesand blood.

Lubricity is, in part, related to biocompatibility andthromboresistance, particularly since the degree of lubricity of acoating is related to wear of the coating due to contact with othersurfaces. For devices, such as needles, sutures, catheters and the like,that transit tissue or abrasive substrates, a high degree of lubricityis desired, concomitant with biocompatibility and a high degree of wearresistance. Thus coatings that are lubricious, but are not resistant tocontact with tissue or abrasive substrates, do not function well inmedical devices.

Long-term use of most polymeric substrates frequently results inmechanical failure, the promotion of blood clot formation, or physicaldegradation due to unfavorable interactions with tissue or bloodenvironments. Thus it is desirable to have coatings or other compositesfor polymeric substrates that are hydrophilic and lubricious, providesuperior strength, do not promote blood clot formation, and which do notinteract with the tissue or blood environment. The specific requirementsof each device vary depending on the degree and duration of contact andthe nature of the application.

Cross-linking of polymers to form a lubricious surface has beenexplored. For example, International Patent Application WO 02/053664,entitled Absorbent, Lubricious Coating and Articles Coated Therewith,discloses a coating consisting of a cross-linked hydrogel copolymerincluding water soluble base polymers with graft polymerized organicmoieties that react with water to form a silanol group, wherein thecopolymer is cross-linked through the silanol groups. However, in thiscoating and method the crosslinking is solely through the silane groups,forming an Si—O—Si cross-link. U.S. patent Application No. 2002/0049281,Process for Cross-Linking Hyaluronic Acid to Polymers, discloses amethod for double crosslinking of hyaluronic acid derivatives,presumably with one bond formed by cross-linking via hydroxyl groups andthe other via, for example, carboxyl groups. However, this methodrequires lengthy reactions, up to forty-eight hours, and extreme pHchanges, ranging from less than pH 4 to pH 12. U.S. Pat. No. 6,169,127,entitled Plasma-Induced Polymer Coatings, discloses coatings for contactlenses utilizing after-glow plasma-induced polymerization of anunsaturated monomeric compound, with cross-linking by concurrentafter-glow plasma-induced polymerization of two monomers, such as aprimary monomeric vinyl compound and a cross-linking agent. This methodrequires co-polymerization of the two monomers, and does not permitprior application of a monomer or polymeric unit to be subsequentlycross-linked or chemical complexation of a monomer or polymeric unit toa linking moiety with the crosslinking subsequent to such complexation.

Prior art coatings employing plasma polymerization are known in the art.These include the coatings and methods disclosed in U.S. Pat. No.5,463,010, to Hu, et al., entitled Hydrocyclosiloxane Membrane PreparedBy Plasma Polymerization Process; and U.S. Pat. No. 5,650,234, toDolence et al., entitled Electrophilic Polyethylene Oxides for theModification of Polysaccharides, Polypeptides (Proteins) and Surfaces.However, these methods do not disclose plasma crosslinking utilizing apolymerizable hydrophilic polymeric unit in conjunction with a plasmaconsisting of a double bond monomer.

None of the preceding references disclose coatings or methods whereinbase hydrophilic polymeric units applied by conventional means, such asdipping, are subsequently cross-linked by plasma polymerization of amonomer, such as a double bond monomer, resulting in a hydrophilic andlubricious coating.

SUMMARY OF THE INVENTION (DISCLOSURE OF THE INVENTION)

In one embodiment the invention provides a plasma cross-linkedhydrophilic and lubricious coating wherein a hydrophilic polymeric unitis cross-linked in situ with a plasma deposited double bond monomer. Thehydrophilic polymeric unit can be an ethylene oxide with one or moreprimary or secondary alcohol groups, including in a preferred embodiment2,2′[(methylethylidine)-bis(4,1-phenyleneoxymethylene)]-bis-oxirane-polymer(PEOC). Alternatively, the hydrophilic polymeric unit can be aglycosaminoglycan, including a long chain linear polysaccharide such ashyaluronic acid, hyaluronan, dextran, cellulose or methyl cellulose.Preferably the double bond monomer includes a C═C, C═N or C═O doublebond, and in a preferred embodiment is N-trimethylsilyl-allylamine(TMSAA), ethylene, propylene or allyl alcohol. The coating can alsoinclude a bifunctional spacer covalently bonded to at least a portion ofthe hydrophilic polymeric unit. In a preferred embodiment, thebifunctional spacer isα-hydro-ω-hydroxypoly(oxy-1,2-ethanediyl)-bis-(1-hydroxbenzotriazolylcarbonate) (HPEOC). The coating can also include a reactive group, suchas a primary or secondary amine, covalently bonded to the bifunctionalspacer. In one embodiment, the hydrophilic polymeric unit and thebifunctional spacer are cross-linked with the plasma deposited doublebond monomer.

The invention further includes a medical device for insertion into thebody of a mammal, which medical device has at least one contactingsurface for contacting bodily fluids or tissues, wherein the contactingsurface has a coating of this invention. The contacting surface mayinclude a metallic or polymeric material. The medical device may be astent, catheter, shunt, valve, pacemaker, pulse generator, cardiacdefibrillator, spinal stimulator, brain stimulator, sacral nervestimulator, lead, inducer, sensor, seed, screw, anchor, anti-adhesionsheet, suture, needle, lens, joint or, in general, any implantablemedical device known or hereafter developed.

The invention further includes a method for coating a surface with ahydrophilic and lubricious coating composition, the method including thesteps of contacting a hydrophilic polymeric unit to the surface to becoated and cross-linking the hydrophilic polymeric unit by plasmadeposition of a double bond monomer. The method may optionally includethe additional steps of introducing a reactive group to the surface andcontacting a bifunctional spacer with the reactive group underconditions whereby the bifunctional spacer is covalently bonded to thereactive group, it being understood that the hydrophilic polymeric unitis contacted to the surface to be coated with the bifunctional spacerunder conditions whereby the hydrophilic polymeric unit is covalentlybonded to the bifunctional spacer. The plasma employed is conventionallya radiofrequency plasma. In a preferred embodiment the plasma depositionis for at least five minutes, and preferably for at least ten minutes.The reactive group may be a primary amine or secondary amine, and if asecondary amine, may include plasma deposition of TMSAA. A primaryobject of the present invention is to provide a method to cross-link apolymeric unit coating by plasma deposition of a double bond monomer,such that a cross-linked lubricious coating results.

Another object of the present invention is to provide a coating that isboth biocompatible and lubricious, including hydrophilic polymeric unitscross-linked by means of a plasma deposited double bond monomer.

Another object of the present invention is to provide a coating withincreased wear and resistance characteristics, resulting from plasmacrosslinking utilizing a double bond monomer.

Another object of the present invention is to provide a coating whereincharacteristics, including lubricity and wear resistance, may be alteredby varying the plasma deposition time or plasma energy, or both, of thedouble bond monomer plasma.

Another object of the present invention is to provide a method forcrosslinking a hydrophilic polymer that does not require pH adjustments,lengthy reaction times or chemical reaction solutions.

Another object of the present invention is to provide a coatingincluding a bifunctional spacer covalently bonded to a reactive groupanchored on a substrate surface, wherein the bifunctional spacers arecross-linked to hydrophilic polymeric units by means of plasma depositeddouble bond monomers.

Another object of the present invention is to provide a hydrophilic andlubricious cross-linked centeral that may be applied to any substrate,including metal, polymeric and ceramic substrates.

Other objects, advantages and novel features, and further scope ofapplicability of the present invention will be set forth in part in thedetailed description to follow, taken in conjunction with theaccompanying drawings, and in part will become apparent to those skilledin the art upon examination of the following, or may be learned bypractice of the invention. The objects and advantages of the inventionmay be realized and attained by means of the instrumentalities andcombinations particularly pointed out in the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated into and form a partof the specification, illustrate one or more embodiments of the presentinvention and, together with the description, serve to explain theprinciples of the invention. The drawings are only for the purpose ofillustrating one or more preferred embodiments of the invention and arenot to be construed as limiting the invention. In the drawings:

FIG. 1 depicts a chemical scheme for plasma deposition of amine reactivegroup, TMSM, on a substrate surface;

FIG. 2 depicts a chemical scheme for reaction of HPEOC with TMSAA;

FIG. 3 depicts a chemical scheme for reaction of PEOC with HPEOC; and

FIG. 4 depicts a chemical scheme for crosslinking PEOC with a plasmadeposited double bond monomer.

DESCRIPTION OF THE PREFERRED EMBODIMENTS (BEST MODES FOR CARRYING OUTTHE INVENTION)

In a first aspect, the invention provides for cross-linking ofhydrophilic polymeric units, such as an ethylene glycol derivative orcomplex carbohydrate, and preferably hydrophilic polymeric unitscontaining either primary or secondary alcohol groups or both, by meansof plasma deposition of a double bond monomer. The hydrophilic polymericunit may be applied in solution, such as by means of a suitable solvent,by conventional means, including spraying, dipping, coating and thelike. The double bond monomer preferably includes a C═C bond, but mayalso include monomers with C═N or C═O bonds. The double bond monomer isapplied by means of plasma deposition, resulting in free radicalformation and C—C bonds cross-linking the hydrophilic polymeric unit,such as through primary or secondary alcohol groups.

In a second aspect, the invention provides a lubricious and hydrophilicbiocompatible coating with enhanced wear characteristics, which coatingincludes cross-linked hydrophilic polymeric units, such as an ethyleneglycol derivative or complex carbohydrate that is cross-linked through aplasma deposition process utilizing a double bond monomer.

In a third aspect, the invention provides a coating wherein two or moreco-polymers are cross-linked through a plasma deposition processutilizing a double bond monomer.

In a fourth aspect, the invention provides a coating including a firstgroup introduced by any means, including plasma deposition, which firstgroup provides a primary amine, secondary amine or other functionalgroup, a second group that is a bifunctional spacer bound, preferably bya covalent bond, to the first group, and at least one third group thatis a hydrophilic polymeric unit bound, preferably by a covalent bond, tothe bifunctional spacer, wherein the at least one third group iscross-linked by means of plasma polymerization of a double bond monomer.The bifunctional spacer may constitute a co-polymer, such that thesecond group bifunctional spacer is cross-linked to the third grouphydrophilic polymeric unit by means of plasma polymerization of thedouble bond monomer.

The process of the invention yields, in a comparatively simple andeasily reproducible manner, smooth and continuous hydrophilic layers ofpolymerized hydrophilic polymeric units. The hydrophilic character ofthe surfaces, detectable from the smaller contact angle, is increasedconsiderably, or provided in the first instance, by the process of theinvention. The process can be carried out with a large number ofdifferent polymeric substrates and various hydrophilic polymeric units.The hydrophilic polymer layers are, in one embodiment, covalently bondedto the substrate, and cannot be detached from the substrate selectivelywith solvents and are therefore very durable. In another embodiment, thehydrophilic polymer layers are covalently bonded to a primer coatingthat is in turn attached to the substrate.

The following terms are defined as follows for the purposes of thisdisclosure:

A “plasma process” includes a capacitively coupled plasma depositionsystem. In one embodiment, a glow discharge is ignited betweenseven-inch square parallel plate electrodes made of aluminum. Thedistance between the two electrodes is 6.5 inches. The electrodes areboth power driven at a radio frequency of 13.56 MHz, and the wholeplasma chamber is grounded. The sample rack is made of Teflon andstainless steel set in the plasma glow zone and is electricallyfloating, and may be rotated during the plasma process to assureuniformity of plasma coating or surface modification on samples.

A “hydrophilic polymeric unit” includes polyethylene glycols (PEG),polyethylene oxides, and derivatives and related compounds thereof, suchas activated PEG, derivatized PEG, and various other water-soluble andnon-peptidic polymers, copolymers, terpolymers and mixtures thereof, andfurther includes glycosaminoglycans, including long chain linearpolysaccharides such as heparin, hyaluronic acid, hyaluronan, cellulose,dextans, and methyl cellulose. Preferably the hydrophilic polymeric unitincludes one or more primary or secondary alcohol groups, such as ahydroxyl group attached to a primary carbon or a hydroxyl group attachedto a secondary carbon. Examples of hydrophilic polymeric units includePEG, polyalkylene glycol, polyoxyethylated polyol, polyolefinic alcohol,polyvinylpyrrolidone, polyvinyl alcohols, polyacrylamines, and the like,as well as glycosaminoglycans such as complex carbohydrates, includingheparin, heparan sulfate, hyaluronic acid, hyaluronan, dextran, dextransulfate, chondroitin sulfate, dermatan sulfate, dextrans, and the like,including but not limited to molecules including a mixture of variablysulfated polysaccharide chains composed of repeating units ofd-glucosamine and either 1-iduronic or d-glucuronic acids, andderivatives of any of the foregoing. One preferred hydrophilic polymericunit is2,2′[(methylethylidine)-bis(4,1-phenyleneoxymethylene)]-bis-oxirane-polymer(PEOC).

A “double bond monomer” includes any molecule that can be applied bymeans of plasma deposition and that contains a double bond, preferably aC═C bond, and less preferably a C═N or C═O bond. The C═C double bond canbe present in most diverse functional groups, for example in alkenylresidues, such as vinyl or allyl residues, or in functional groupsderived from unsaturated carboxylic acids or derivatives thereof, suchas acrylic acid, methacrylic acid, the amides of these carboxylic acidsor maleic acid. These compounds can also contain hydrophilic groups suchas amine groups, acyloxy groups, carboxyl groups, carboxylic acid estergroups, carboxylic acid amide groups, carboalkoxy groups, nitrilegroups, 1,2-epoxide groups, sulfuric acid esters and sulfonic acid,sulfinic acid, phosphoric acid, phosphonic acid and phosphinic acidgroups, including their corresponding salts and esters, primary,secondary and tertiary amino groups, and acylamino groups, which can beincorporated as an open chain or in ring-polyalkylene oxide groups. Thebalance between hydrophilic and hydrophobic contents in the monomerdetermines the hydrophilicity of the monomer, and thus this factor maybe utilized in determining a suitable monomer for a given purpose.Monomers that are suitable for use in this invention include gases,volatile liquids, or molecules that can be made to become volatile suchthat they can be introduced into a glow discharge plasma chamber.Examples of suitable monomers which may be utilized include propylene;ethylene; acrylic acid and derivatives thereof, such as for exampleacrylamide, N,N-dimethylacrylamide, acrylonitrile, methyl acrylate,2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 2-methoxyethylacrylate, 2-ethoxyethyl acrylate, 4-hydroxybutyl acrylate and1,4-butanediol diacrylate; methacrylic acid and correspondingderivatives thereof; carboxylic acid vinyl derivatives, such as forexample vinyl acetate, N-vinylacetamide,N-vinylpyrrolidone-vinylsulfonic acids and alkali metal salts thereof,such as sodium vinylsulfonatealkenylarylsulfonic acids; styrene, styrenesulfonic acid and styrene sulfonate-vinyl ethers, such as vinyl methylether, vinyl ethyl ether, vinyl glycidyl ether, diethylene glycoldivinyl ether and vinyl n-butyl ether; vinyl ketones, such as vinylmethyl ketone, vinyl ethyl ketone and vinyl n-propyl ketone;vinylamines, such as N-vinylpyrrolidine; polyalkylene compounds withterminal allyl, vinyl, acrylic or methacrylic groups, such asethoxytetraethoxyethyl acrylate or methacrylate, allylamine, allylalcohol, propylene, ethylene, and the like. It is contemplated thattriple bond monomers are included within the definition of double bondmonomers, so that triple bond monomers such as acetylene can alsoemployed. A preferred double bond monomer is N-trimethylsilyl-allylamineof the formula CH₂═CH—CH₂—NH—Si(CH₃)₃ (TMSAA), which includes a C═Cbond. Other preferred double bond monomers include ethylene (CH₂═CH₂),propylene (CH₂═CH—CH₃) and allyl alcohol (CH₂═CH—CH₂—OH). The doublebond monomer can constitute a hydrophilic polymeric unit as definedabove, provided it contains at least one double bond.

A “bifunctional spacer” is a molecule that can be bound by any means totwo different molecules, such as a functional group on a substrate and ahydrophilic polymeric unit. A bifunctional spacer preferably formscovalent bonds with amine groups, and further preferably constitutes ahydrophilic polymeric unit. The bifunctional spacer can be any of anumber of bifunctional agents that react with amines, such asbis-variants of PEG, polyethylene oxide, and related PEG compoundswherein the functional groups are composed of homo- or hetero-functionalgroups, with representative functional groups including succinimymidylesters, nitrophenyl activated esters, azidophenyl groups, maleimidogroups, imido esters, carbodiimides, benzotriazole carbonates, oraldehdye groups. A preferred bifunctional spacer isα-hydro-ω-hydroxypoly(oxy-1,2-ethanediyl)-bis-(1-hydroxbenzotriazolylcarbonate) (HPEOC), which contains benzotriazole carbonate functionalgroups.

A “substrate” is any surface to be coated by the method of thisinvention, or with the coating of this invention. Substrates thusinclude homo- and co-polymers, for example polyolefins, such aspolyethylene, polypropylene, polyisobutylene, polybutadiene,polyisoprene; naturally occurring rubbers and polyethylene-copropylene;halogen-containing polymers, such as polyvinyl chloride, polyvinylidenechloride, polychloroprene, polytetrafluorothylene and polyvinylidenefluoride; polymers and co-polymers of vinylaromatic monomers, such aspolystyrene, polyvinyloluene, polystyrene-co-vinyltoluene,polystyrene-co-acrylonitrile andpolystyrene-co-butadiene-co-acrylonitrile; polycondensates, such aspolyesters like polyethylene terephthalate and polybutyleneterephthalate; polyamides, such as polycaprolactam, polylaurolactam andthe polycondensate of adipic acid and hexamethylenediamine;polyether-block amides, such as laurolactam and polyethylene glycol withon average 8-, 12- or 16-ethyleneoxy groups; poly caprolactone; polylactide; polyglycolide, and generally polyurethanes, polyethers,polycarbonates, polysulfones, polyether ketones, polyester-amides and-imides, polyacrylonitrile and polyacrylates and polymethacrylates.Blends of two or more polymers or co-polymers can also be coated by themethod of this invention, as can combinations of various plastics thatare joined to one another by adhesive bonding, welding or fusion,including the transition regions. A substrate also includes metals, suchas stainless steel, nitinol, titanium, and blends or composites thereof,and ceramics.

The substrate may form a surface structural component of a medicaldevice intended to contact blood or other tissues, such as stents,needles, sutures, catheters, shunts, grafts, and other medical devicesknown in the art. The surface structural component may include a plate,curved surfaces, mesh, coil, wire, inflatable balloon, or any otherdevice or structure which is capable of being implanted at a targetlocation, including intravascular target locations, intralumenal targetlocations, target locations within solid tissue, such as for thetreatment of tumors, and the like. The device can be intended forpermanent or temporary implantation. Such devices may be delivered by orincorporated into intravascular and other medical catheters.

The methods and coatings of the invention find primary application inmedical devices, and particularly blood- or tissue-contacting medicaldevices wherein lubricity is desired, such as grafts, catheters,guidewires, sutures, needles, stents and the like. The coating providesa surface with good handling characteristics when dry, but which becomeslubricious upon contact with an aqueous solution, such as a bodilyfluid. However, the methods and coatings of the invention can be usedwith other medical devices wherein lubricity is desired, includingcontact lenses, bandages and other wound covers, and the like, as wellas in pharmaceutical, cosmetic and other applications where lubricity,particularly coupled with biocompatibility, is desired on one or moresurfaces.

In one embodiment, secondary amine groups are introduced onto thesurface of a substrate by plasma deposition of a secondaryamine-containing substance, such as TMSAA, as is shown in the scheme ofFIG. 1. In FIG. 1, TMSAA is shown attached to a substrate by means of aplasma, resulting in a secondary amine with a terminal —Si(CH₃)₃ groupthat can be cleaved by means of an aqueous media. For example,polyethylene and similar polymeric substrates can be so treated withTMSAA to introduce reactive amines. TMSAA is integrated by plasmagrafting using operational parameters sufficient to introduce therequisite density of secondary amine groups without adverse surfacemodification. Plasma grafting may proceed at, for example, operationalparameters of 8 minutes deposition time at 65 mTorr, 45 W and a flowrate of TMSAA of 42 standard cubic centimeters per minute (sccm).Alternative methods of introducing primary or secondary amines can alsobe utilized, including plasma processes to introduce primary aminegroups into a surface using ammonia gas in a plasma chamber, asdescribed in U.S. Pat. No. 5,338,770, and various chemical modificationmethods, as described in U.S. Pat. No. 6,265,016, entitled Process forthe Preparation of Slippery, Tenaciously Adhering, HydrophilicPolyurethane Hydrogel Coatings, Coated Polymer and Metal SubstrateMaterials, and Coated Medical Devices, such as use of aminosilanes.

For certain applications, such as metal-containing substrates,glow-discharge plasma treatment with a siloxane derivative, such as1,3,5,7-tetramethylhydrocyclo-tetrasiloxane (TMCTS), followed byintegration by plasma grafting of an amine-rich reagent, such as TMSAA,is preferred. The plasma process with TMCTS creates a “primer” coatingof polymeric TMCTS. In this embodiment, any hydrocyclsiloxane monomermay be employed, including 1,3,5,7-tetramethylhydrocyclotetrasiloxane,1,3,5,7,9-pentamethylhydrocyclopentasiloxane,1,3,5,7,9,11-hexamethylhydrocyclohexasiloxane, or a mixture of1,3,5,7,9-pentamethylcyclopentasiloxane and1,3,5,7,9,11-hexamethylcyclohexasiloxane monomers, as taught in U.S.Pat. No. 5,463,010, incorporated herein by reference. In a relatedembodiment, the surface, with metal or polymeric surfaces, may beinitially modified using nitrogen- and oxygen-containing plasma astaught in International Patent Application PCT/US00/34945,Plasma-Deposited Coatings, Devices and Methods, incorporated herein byreference.

Following introduction of a primary or secondary amine to the surface ofthe substrate, the substrate may be washed with a suitable organicsolvent prior to proceeding with further reactions. Depending on thesubstrate and the primary or secondary amine group introduced, suitableorganic solvents include methylene chloride, acetonitrile and the like.

A bifunctional spacer may then be attached to the primary or secondaryamine, as is shown generally in the scheme of FIG. 2, depicting additionof HPEOC and cleaving of the —Si(CH₃)₃ group, resulting in PEOCconjugated by means of a covalent bond to the introduced secondaryamine, the PEOC sequence further including a terminal benzotriazolecarbonate group at the distal end. A preferred bifunctional spacer isHPEOC, which can be applied by immersing the surface in a solutionincluding HPEOC. In one embodiment, 5% HPEOC in acetonitrile isemployed; in another embodiment 5% HPEOC in methylene chloride isemployed. The HPEOC reacts with the secondary amine on the surfaceresulting in conjugation, such that one functional group on the HPEOC isutilized for the covalent bond with the secondary amine. HPEOC istypically supplied in methylene chloride and is utilized in a largemolar excess, such that the conjugated agent consumes only onefunctional group. Unreacted bifunctional spacer may be removed, such asby rinsing in a suitable solvent.

A hydrophilic polymeric unit is then added, such as by dipping orimmersing the bifunctional spacer complexed surface in a solutionincluding the hydrophilic polymeric unit. Where PEOC is employed as thehydrophilic polymeric unit, a 10% solution may be employed. The monomerscan be used individually or as a mixture adapted to the particularintended use. A coating of a homo- or co-polymer is obtained accordinglyon the substrate. The monomers are in general employed as 1% to 40%,advantageously as 5% to 20%, strength by weight solutions. Aconventional solvent that can be employed is methylene chloride. Thescheme of FIG. 3 illustrates the reaction of the hydrophilic polymericunit PEOC with the remaining functional group of the surface-boundbifunctional spacer HPEOC, resulting in both covalently complexedrepeating PEOC units and PEOC associated therewith but not covalentlycomplexed thereto. The hydrophilic polymeric unit is preferably appliedat a concentration such that a thin film of unreacted hydrophilicpolymeric unit is left as an overcoating. The thin film is dried ontothe surface.

As is shown in the scheme of FIG. 4, a double bond monomer, depicted asR—C═C—R, is reacted with the hydrophilic polymeric unit by means of aplasma, resulting in crosslinking of the hydrophilic polymeric unit inthe thin film, including crosslinking with hydrophilic polymeric unitsbound to the bifunctional spacer and the underlying bifunctional spacer,if provided. While FIG. 4 illustrates crosslinking between adjacent PEOCunits not covalently complexed and between covalently complexed PEOC anduncomplexed PEOC, it is to be understood that the reaction as depictedin FIG. 4 can further include crosslinking between any of the foregoingand the bifunctional spacer, such as the PEOC resulting fromcomplexation of the HPEOC bifunctional spacer. It is hypothesized,without wishing to be bound by theory, that crosslinking is primarilythrough primary or secondary alcohols, or both, in the hydrophilicpolymeric unit, effected by free radicals formed by the double bondmonomer plasma. Thus, for example, if PEOC is the hydrophilic polymericunit and HPEOC is the bifunctional spacer, it may readily be seen thatcrosslinking is possible between parallel PEOC chains, betweencovalently complexed PEOC and free PEOC, such as through an alcohol orthrough activation and displacement of a benzotriazole group, andbetween either complexed PEOC or free PEOC and HPEOC, again throughsimilar groups.

TMSAA is a preferred double bond monomer because the compound can alsobe used to introduce secondary amine groups, and because thetrimethylsilyl group functions as a protecting group, in that it isspontaneously cleaved in an aqueous environment, but is stable in plasmaprocesses, and thus prevents inadvertent crosslinking between amines.

It has been discovered that, in general, a longer plasma process atlower energy results in more crosslinking, and apparently improvedlubricity, than a shorter plasma process at higher energy. Thus, forexample, in one embodiment TMSAA plasma for 10 minutes at 45 W, 65 mTorrand 42 sccm is employed. The plasma process parameters may be modifiedto produce the desired effect using the methods and examples describedherein.

While for many applications introduction of a reactive amine or othergroup and attachment of a bifunctional spacer provides advantageousresults, for other applications it may only be necessary to apply thehydrophilic polymeric unit and subsequently cross-link in situ thepolymeric units by means of a double bond monomer plasma. That is, theinvention includes films, coatings and other compositions wherein ahydrophilic polymeric unit is applied without utilizing a bifunctionalspacer or introducing a reactive group.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLE 1 TMSAA Plasma Grafting and HPEOC Reaction

Strips of polyethylene were used as the substrate. TMSAA was integratedonto the plastic by plasma grafting with operational parameters of 8minutes deposition time at 65 mTorr, 45 W, and a flow rate of 42 sccm.The TMSAA plasma grafted strips were rinsed for 5 minutes in methylenechloride, and then immersed in a solution of 5% HPEOC in methylenechloride for 20 minutes. Unreacted HPEOC was removed in a 5 minute rinsein methylene chloride.

EXAMPLE 2 Stainless Steel Modification

Stainless steel wafers (0.75 cm×0.75 cm) were treated in aglow-discharge plasma with a mixture of NH₃/O₂ for 45 seconds. Theplasma was generated at 110 W and pressure of 50 mTorr using a totalmass flow rate of 50 sccm. The materials were then treated byglow-discharge plasma with the siloxane derivative TMCTS for 4 seconds,causing the TMCTS to polymerize and attach to the substrate. The TMCTSplasma was generated at 83 W, 55 mTorr, and a flow rate of 84 sccm.TMSAA was then integrated into the film by plasma grafting withoperational parameters of 4 minutes of deposition time, 65 mTorr, 35 W,and a flow rate of 42 sccm. The resulting coated steel wafers wererinsed for 5 minutes in methylene chloride. The wafers were immersed ina solution of 5% HPEOC in methylene chloride for 20 minutes. UnreactedHPEOC was removed in a 5 minute rinse in methylene chloride.

EXAMPLE 3 TMSAA Crosslinking of PEOC/HPEOC

Strips of polyethylene were used as the substrate. TMSAA was integratedonto the plastic by plasma grafting with operational parameters of 8minutes of deposition time, 65 mTorr, 45 W, and a flow rate of 42 sccm.The TMSAA plasma-grafted polyethylene strips were then rinsed for 5minutes in methylene chloride, followed by immersion in a solution of 5%HPEOC in methylene chloride for 20 minutes. Unreacted HPEOC was removedin a 5 minute rinse in methylene chloride. The HPEOC reactedpolyethylene strips were then immersed in a 10% solution of PEOC for 20minutes and air-dried. The PEOC and HPEOC were then cross-linked in aplasma process using plasma crosslinking with TMSAA as the crosslinkingagent. The TMSAA cross-linked plasma had operational parameters of 16minutes of deposition time, 65 mTorr, 45 W, and a flow rate of 42 sccm.The materials were then immersed in methylene chloride for 5 minutes andair-dried.

EXAMPLE 4 TMSAA Crosslinking of Hyaluronic Acid

Strips of polyethylene were used as the substrate. TMSAA was integratedonto the plastic by plasma grafting with operational parameters of 4minutes of deposition time, 65 mTorr, 45 W, and a flow rate of 42 sccm.The TMSAAS plasma-grafted polyethylene strips were then rinsed for 5minutes in methylene chloride, followed by immersion in a solution of 5%HPEOC in methylene chloride for 20 minutes. Unreacted HPEOC was removedin a 5 minute rinse in methylene chloride. The HPEOC reactedpolyethylene strips were then immersed in a 0.5% solution of hyaluronicacid for 20 minutes and air-dried. The resulting product wascross-linked in a plasma process using plasma crosslinking with TMSAA asthe crosslinking agent. TMSAA plasma had operational parameters of 16minutes of deposition time, 65 mTorr, 45 W, and a flow rate of 42 sccm.The materials were then immersed in methylene chloride for 5 minutes andair-dried.

EXAMPLE 5 Guide Wire TMSAA Crosslinking of PEOC/HPEOC

Guide wires were treated in a glow-discharge plasma with a mixture ofNH₃/O₂ for 45 seconds. The plasma was generated at 110 W under a vacuumof 50 mTorr and using a total mass flow rate of 50 sccm. The materialswere then treated by glow-discharge plasma with the siloxane derivativeTMCTS for 4 seconds, resulting in TMCTS polymeri attached to thesubstrate. The TMCTS plasma was generated at 83 W, 55 mTorr, and flowrate of 84 sccm. TMSAA was then integrated into the film by plasmagrafting using operational parameters of 4 minutes of deposition time,65 mTorr, 35 W, and a flow rate of 42 sccm. The coated wires were thenrinsed for 5 minutes in acetonitrile, followed by immersion in asolution of 5% HPEOC in acetonitrile for 20 minutes. Unreacted HPEOC wasremoved in a 5-minute rinse in acetonitrile. The coated wires were thenimmersed in a 10% solution of PEOC for 20 minutes and air-dried. Thesurface of the coated wires was cross-linked in a plasma process usingTMSAA as the crosslinking agent. The TMSM plasma had operationalparameters of 12 minutes of deposition time, 65 mTorr, 45 W, and a flowrate of 42 sccm. The materials were then immersed in acetonitrile for 5minutes and air dried.

EXAMPLE 6 Double Bond Monomers

To evaluate the critical effect of monomers containing at least onedouble bond on plasma crosslinking of PEOC, three different monomerswere used on HPEOC/PEOC coated stainless steel substrates: ethylene(CH₂═CH₂), ethane (CH₃—CH₃), and allyl alcohol (CH₂═CH—CH₂—OH).Stainless steel strips (1″×3″) were used as the substrate. Strips werefirst overlayered with a siloxane polymer y plasma treatment inglow-discharge plasma of NH₃O₂ followed by treatment in a plasma ofTMCTS. The NH₃/O₂ plasma was generated for 45 seconds at 110 W at apressure of 50 mTorr and a total mass flow rate of 50 sccm; the TMCTSplasma for 4 seconds at 83 W, 55 mTorr, with a flow rate of 84 sccm.TMSAA was integrated into the substrate for 4 minutes using operationalparameters of 65 mTorr, 35 W, and a mass flow rate of 42 sccm. Theplasma-coated stainless steel strips were rinsed for 5 minutes inmethylene chloride, dip-coated in a solution of 5% HPEOC in methylenechloride for 20 minutes, and rinsed for 5 minutes in methylene chlorideto remove unreacted HPEOC. After the final rinse, the HPEOC reactedstainless steel strips were dip-coated in a 10% solution of PEOC inmethylene chloride for 20 minutes and dried in air.

The coated steel strips were exposed to a plasma formed with one ofethylene, ethane, or allyl alcohol. Three different plasma parameterswere used for each different monomer: (1) 45 W, 6 minutes, 65 mTorr and42 sccm; (2) 45 W, 10 minutes, 65 mTorr and 42 sccm; and (3) 90 W, 6minutes, 65 mTorr and 42 sccm. After plasma process, the resultingcoated steel strips were rinsed in running de-ionized water for 20minutes and air dried.

A comparison of surface lubricity was made and the results indicatedthat plasmas of ethylene and allyl alcohol produced crosslinking on thePEOC surface and substantially improved lubricity. The most favorablecondition for high crosslinking was at a lower power and longer time,that is, 45 W for 10 minutes, at 65 mTorr and a flow rate of 42 sccm.The ethane plasma did not provide any improvement on surface lubricity,and actually decreased lubricity compared to coated strips without thelast plasma step. In a separate test, propylene (CH₂═CH—CH₃) yieldedresults comparable to ethylene or TMSAA.

EXAMPLE 7 Pull Force Testing

Pull force testing was performed on polyethylene strips with and withoutthe coating as in Example 3. The pull force was measured with a tensilestrength monitor (Instron). The pulling force was determined as theaverage load in pounds needed to displace the strip from an initialsetting of 0.3″ to a final position of 1.1″ under wet conditions.Polyethylene samples with no coating (controls) required an averageforce of 6.413 lbs to affect displacement. Polyethylene samples treatedwith the TMSAA cross-linked PEOC coating as in Example 3 required anaverage force of 0.671 lbs.

EXAMPLE 8 Reduction of Pulling Force by Increasing TMSAA PlasmaTreatment Time

Polyethylene specimens were processed as in Example 3 except that thetime of the final TMSAA plasma was varied in 4-minute intervals from 4minutes to 16 minutes. The specimens were then subjected to pull-forcetesting as in Example 7. The data was then converted to percentages.Increasing the time of the TMSAA crosslinking plasma decreased the forceneed to affect displacement. Plasma times of 4-, 8-, 12-, and 16 minutesresulted in a decrease in force relative to uncoated specimens of 75.0%,83.7%, 84.8%, and 87.0%, respectively.

EXAMPLE 9 Effect of Varying Wattage of TMSAA Plasma Treatment

Stainless steel specimens were processed as in Example 5 except that thewattage used in the final TMSAA crosslinking plasma treatment was either35 W or 45 W. The specimens were tested by pull force testing as inExample 7. With no treatment, the mean pulling force was 5.637 lb/f.Using the coating procedure and 45 W in the final TMSAA crosslinkingstep, the mean pulling force was reduced by 91.2% to 0.497 lbs. Usingthe coating procedure and 35 W in the final TMSAA crosslinking step, themean pulling force was reduced by 89.1% to 0.613 lbs.

EXAMPLE 10 Durability of Coating

Polyethylene specimens were processed as in Example 3. The specimenswere tested by pull force testing as in Example 7. The forcemeasurements were serially repeated for 5 pulls and the average pullload is presented in Table 1; the data indicates that the coating isdurable over the testing cycle.

TABLE 1 HPEOC AS THE HYDROPHILIC POLYMERIC UNIT PULL NUMBER AVERAGE PULLLOAD IN lb/f 1 0.671 2 0.850 3 0.840 4 0.803 5 0.807

Polyethylene specimens were processed as in Example 4. The specimenswere tested by pull force testing as in Example 7. The forcemeasurements were serially repeated for 5 pulls and the average pullload is presented in Table 2; the data indicates that the coating isdurable over the testing cycle.

TABLE 2 HYALURONIC ACID AS THE HYDROPHILIC POLYMERIC UNIT PULL NUMBERAVERAGE PULL LOAD IN lb/f 1 0.298 2 0.298 3 0.332 4 0.340 5 0.324

EXAMPLE 11 Surface Lubricity Testing

310 stainless steel straps (1″×3″) were used, with initially cleaningusing Acationox™ detergent and rinsing. Strips were divided into groups,with treatment as shown below. A surface lubricity test was performedusing an Imada, Inc. DPS-0.5 digital force gauge with measurementcontrolled with Imada SW-1 data acquisition software. The digital forcegauge was mounted on a stepping motor driven system, such that thedigital force gauge could be moved at a constant speed. A metal flathead weighing 22 g with a rubber layer was used as the load pad, withsamples placed in a container filled with distilled water and the loadpad placed on the sample surface. Pulling force was measured by pullingthe load pad; the lower the pulling force, the better lubricity. Resultsare shown in Table 3.

TABLE 3 Pulling force Number of Newton Number samples Coating ConditionsMean Std Dev of pulls tested Plasma Coating/HPEOC/PEOC 0.0281 0.0126 323 Plasma Coating/HPEOC/PEOC/ 0.0219 0.0024 3 10 TMSAA HPEOC/PEOC 0.07430.0046 30 3 HPEOC/PEOC/TMSAA 0.0214 0.0021 30 3 HPEOC/TMSAA 0.02460.0016 30 3 PEOC/TMSAA 0.0393 0.0062 30 3 HPEOC only 0.0261 0.0037 30 3TMSAA only 0.2038 0.0218 30 3 SS Control (Clean Sample) 0.157 0.034 3 7

In Table 3, “Plasma Coating” consists of three steps: NH₃/O₂ etching for45 seconds, TMCTS plasma coating for 4 seconds and TMSAA plasmagrafting, all as in Example 2; “HPEOC” consists of dip coating in 5%HPEOC in methylene chloride for 20 minutes as in Example 2; “PEOC”consists of dip coating in 10% PEOC in methylene chloride for 20 minutesas in Example 6; and “TMSAA” consists of a cross-linking process at 45W, 65 mTorr, 42 sccm for 10 minutes as in Example 6. The best resultswere obtained with HPEOC/PEOC/TMSAA (0.0214±0.0021) and PlasmaCoating/HPEOC/PEOC/TMSAA (0.0219±0.0024); however, HPEOC/TMSAA yieldedgood results (0.0246±0.0016). While Plasma Coating/HPEOC/PEOC yieldedmean values approximating the foregoing, the standard deviation in theabsence of crosslinking was unacceptably high.

EXAMPLE 12 Surface Durability Test

Stainless steel strips as in Example 11 were prepared and subjected todurability testing. The results are shown in Table 4.

TABLE 4 % Increase Pulling force Pulling force from 2nd of 2nd pull of30th pull to 30th Coating Conditions Mean Std Dev Mean Std Dev pullPlasma Coating/ 0.0353 0.0037 0.0515 0.0107 46% HPEOC/PEOC PlasmaCoating/ 0.0237 0.0048 0.0281 0.0016 19% HPEOC/PEOC/ TMSAA HPEOC/PEOC0.0596 0.0039 0.079 0.0058 33% HPEOC/PEOC/ 0.0177 0.0005 0.0215 0.001821% TMSAA HPEOC/TMSAA 0.0218 0.0039 0.0232 0.0012  6% PEOC/TMSAA 0.02550.0013 0.0414 0.0078 62% HPEOC only 0.0209 0.0017 0.0303 0.0035 45%TMSAA only 0.2168 0.0068 0.1951 0.0132 −10%  “Coating Conditions” havethe meanings given in Example 11.

EXAMPLE 13 Surface Lubricity of Stainless Steel Wire

Stainless steel wire samples, 5″ long by 0.015″ diameter, were preparedas in Example 11. The results obtained using the methods of Example 11are shown in Table 5.

TABLE 5 Pulling % Coating force Standard Decrease Conditions Tests(Newton) Mean Deviation (v. Control) Clean wire 1 0.2252 0.2377 0.0211 0% (Control) 2 0.2621 3 0.2259 Plasma Coating/ 1 0.1972 0.1890 0.014720% HPEOC/PEOC 2 0.1977 3 0.1720 Plasma Coating/ 1 0.0338 0.0288 0.004488% HPEOC/PEOC/ 2 0.0261 TMSAA 3 0.0264 “Coating Conditions” have themeanings given in Example 11.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

Although the invention has been described in detail with particularreference to these preferred embodiments, other embodiments can achievethe same results. Variations and modifications of the present inventionwill be obvious to those skilled in the art and it is intended to coverin the appended claims all such modifications and equivalents. Theentire disclosures of all references, applications, patents, andpublications cited above are hereby incorporated by reference.

What is claimed is:
 1. A plasma cross-linked hydrophilic and lubriciouscoating comprising a hydrophilic polymeric unit cross-linked in situwith a plasma deposited double bond monomer.
 2. The coating of claim 1wherein the hydrophilic polymeric unit comprises an ethylene oxide withone or more primary or secondary alcohol groups.
 3. The coating of claim2 wherein the hydrophilic polymeric unit comprises2,2′[(methylethylidine)-bis(4,1-phenyleneoxymethylene)]-bis-oxirane-polymer(PEOC).
 4. The coating of claim 1 wherein the hydrophilic polymeric unitcomprises a glycosaminoglycan.
 5. The coating of claim 4 wherein thehydrophilic polymeric unit comprises a long chain linear polysaccharideselected from the group consisting of heparin, hyaluronic acid,hyaluronan, dextran, cellulose and methyl cellulose.
 6. The coating ofclaim 1 wherein the double bond monomer comprises a C═C, C═N or C═Odouble bond.
 7. The coating of claim 6 wherein the double bond monomercomprises a member selected from the group consisting ofN-trimethylsilyl-allylamine (TMSAA), ethylene, propylene and allylalcohol.